The major barriers to preventing or treating Alzheimer's disease (AD) are its unknown pathogenesis/etiology and the lack of an objective, sensitive and specific biomarker of the disease, particularly at the early stages when therapeutic interventions would likely have the greatest efficacy. The basic hypothesis of this application is that plasma levels of a novel aberrant protein/protein complex consisting or lipocalin (brain-specific) prostaglandin-d- synthase (PDS) and transthyretin (TTR) are decreased early in disease progression and that baseline (pre-conversion) PDS/TTR levels are significantly lower in subjects who transition to mild cognitive impairment (MCI) or AD compared to normal control (NC) subjects or subjects with non-AD neurodegenerative disorders. As such, plasma PDS/TTR concentrations can be used to preferentially identify subjects who are likely to transition to MCI or AD. Preliminary analysis of antemortem plasma samples from 76 NC and 45 MCI subjects showed a statistically significant decrease of PDS/TTR levels in MCI. In addition, analysis of plasma PDS/TTR concentrations in normal subjects who later converted to MCI showed PDS/TTR concentrations before conversion were significantly (32 percent) lower than levels in plasma from NC subjects who remained cognitively normal during a comparable follow-up period. Although our preliminary data are promising and suggest PDS/TTR concentrations may be used to identify and predict subjects who will convert to dementia, further study is needed. To further test our hypothesis, we will analyze plasma samples from additional 80 - 100 samples from each group (NC, MCI and probable AD). We will also test whether plasma PDS/TTR complex concentrations decrease in the same person following conversion to MCI or AD by analyzing pre- and post-conversion specimens from NC subjects who transitioned from normal to MCI (n = 83) or AD (n = 32) compared to results obtained for plasma samples from control subjects who remained cognitively normal (n = 360) after a comparable follow-up period. Plasma specimens will also be analyzed from subjects with non-AD neurodegenerative diseases including frontotemporal dementia and diffuse Lewy body disease. In addition, we will test whether pre-conversion PDS/TTR concentrations alone, or in combination with A1-42, A1- 40, measures correlate with or enhance identification of MCI/AD patients based on Mini Mental State Examination (MMSE) and specific memory scores (Animal fluency, Trials A, Trials B and logical memory (logmemL)). Overall, the proposed studies, if successful, will identify and validate a novel blood based biomarker of AD that can be used to identify subjects early in disease progression when pharmacologic interventions likely have the greatest efficacy. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the sixth leading cause of death in the United States and currently affects 4.5 million Americans. Two major barriers to treating and eventually preventing AD are: 1) the lack of understanding about the process of neuron degeneration and loss and 2) the lack of a sensitive and specific biomarker of the disease. Preliminary and future studies described in this application show that a novel protein-protein complex present in serum can be quantified using an enzyme linked immunoassay (ELISA). This protein-protein complex is a sensitive and specific biomarker of AD including early stages of AD when therapeutic interventions are most likely to have beneficial effects.